Long Term, Extension Study of the Safety and Efficacy of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

The ESS is an 8-item questionnaire that is used to measure sleepiness by rating the probability of falling asleep on 8 different situations that most people engage in during the day. The 8 questions are rated on a 4-point scale (0 to 3) where 0 = would never doze, 1 = slight chance of dozing, 2 = moderate chance of dozing, and 3 = high chance of dozing. The scores are summed to give an overall score of 0 to 24. A total score of 0 to 9 is considered to be normal. Higher score indicates greater daytime sleepiness. Negative change from baseline indicate improvement in daytime sleepiness.

Time frame: Baseline (current study), Week 52

Population: Safety population included all participants who received the study treatment. 'Overall number of participants analyzed' indicates the number of participants evaluable for the outcome measure at the specified time point.

The MMSE is a brief questionnaire that is used to assess cognitive impairment and severity of cognitive impairment. The MMSE scale comprises 11 questions or simple tasks concerning orientation, memory, attention, and language to evaluate a participant's cognitive state and are scored as follows: Orientation to Time - 0 to 5; Orientation to Place - 0 to 5; Registration - 0 to 3; Attention and Calculation - 0 to 5; Recall - 0 to 3; Naming - 0 to 2; Repetition - 0 to 1; Comprehension - 0 to 3; Reading - 0 to 1; Writing - 0 to 1; Drawing - 0 to 1. The total score was calculated by summing all of the item scores and ranges from 0 to 30. Higher scores indicate milder cognitive impairment. Negative change from baseline indicates decline in cognitive performance.

Time frame: Baseline (current study), Week 52

Population: Safety population included all participants who received the study treatment. 'Overall number of participants analyzed' indicates the number of participants evaluable for the outcome measure at the specified time point.

The S-STS is a prospective scale that assesses treatment-emergent suicidal thoughts and behaviors. This is a 20-item scale where each item (except item 17) of the S-STS is scored on a 5-point Likert scale as: 0 = Not at all, 1 = A little, 2 = Moderate, 3 = Very, 4 = Extremely. The S-STS total score is calculated by the sum of items 1a (if present), items 2-11, highest score of item 12 or 16, highest score of item 14 or 15, item 17 and 20. The total score ranges from 0 to 156 (If response to S-STS item 17 =yes, a score of 100 was added to the S-STS total score). Higher scores indicate greater severity of suicidal ideation and/or behavior. A negative change from baseline reflects a reduction in suicidal thoughts or behaviors over time.

Time frame: Baseline (current study), Week 64

Population: Safety population included all participants who received the study treatment. 'Overall number of participants analyzed' indicates the number of participants evaluable for the outcome measure at the specified time point.

The physical examination included assessments of head, eyes, ears, nose, throat, lymph nodes, skin, extremities, respiratory, gastrointestinal, musculoskeletal, cardiovascular, and nervous systems. The neurological examination included assessments of mental status, cranial nerves, motor system, reflexes, coordination, gait and station, and sensory system.

Time frame: Baseline (current study), Week 52

Population: Safety population included all participants who received the study treatment.

A resting 12-lead ECG was performed for all the participants. ECG data included PR interval (milliseconds {msec}) and QTcF (msec) along with change from baseline in QTcF. Number of participants with potentially clinically significant ECG abnormalities was reported as per the criteria defined in SAP.

Time frame: Baseline (current study) up to 52 weeks

Population: Safety population included all participants who received the study treatment. 'Overall number analyzed' indicates the unique participants who were evaluated for this outcome measure. 'Number analyzed' indicates the number of participants evaluable for the specific category.

Vital signs measurements included systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Blood pressure (i.e., SBP, DBP) and heart rate were measured in the supine and standing positions after the participant had been in each position for at least 5 and 3 minutes, respectively. Number of participants with clinically significant vital sign abnormalities were reported as per criteria defined in SAP. The categories with at least one participant with clinically significant vital signs abnormalities are reported here.

Time frame: Baseline (current study) up to 52 weeks

Population: Safety population included all participants who received the study treatment. 'Overall number analyzed' indicates the unique participants who were evaluated for this outcome measure. 'Number analyzed' indicates the number of participants evaluable for the specific category.

Laboratory assessments included clinical chemistry (alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, cholesterol, creatinine kinase, creatinine, gamma glutamyl transferase, glucose, lactate dehydrogenase, magnesium, protein, potassium, sodium, triglycerides and uric acid), hematology (basophils, eosinophils/leukocytes, erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, lymphocytes/leukocytes, monocytes, monocytes/leukocytes, neutrophils/leukocytes, platelets). Number of participants with clinically significant laboratory test abnormalities were reported as per criteria defined in statistical analysis plan (SAP). The categories with at least one participant with potentially clinically significant laboratory values are reported.

Time frame: Baseline (current study) up to 52 weeks

Population: Safety population included all participants who received the study treatment. 'Overall number analyzed' indicates the unique participants who were evaluated for this outcome measure. 'Number analyzed' indicates the number of participants evaluable for the specific category.

A serious adverse event (SAE) is any AE occurring at any dose that results in death, life-threatening experience, persistent or significant disability/incapacity, in-patient hospitalization or prolongation of hospitalization or congenital anomaly/birth defect. A serious TEAE is defined as AE that occurred or worsened after the first dose of study treatment up until 30 days after last dose.

Time frame: From first dose of study drug (in current study) up to 3 months after last dose of study drug (up to Week 64)

Population: Safety population included all participants who received the study treatment.

An adverse event (AE)is any untoward medical occurrence or unintended change (e.g. physical, psychological, or behavioral), including inter-current illness, whether considered related to treatment or not. An AE can therefore be any unfavorable and unintended sign (including any clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A TEAE is defined as an AE that occurred or worsened after the first dose of study treatment up until 30 days after last dose.

Time frame: From first dose of study drug (in current study) up to 3 months after last dose of study drug (up to Week 64)

Population: Safety population included all participants who received the study treatment.

The NPI is a validated clinical instrument used to assess neuropsychiatric symptoms. It evaluates 12 neuropsychiatric symptom domains including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime behavioral disorders, and appetite/eating disorders. Each symptom domain is rated by the caregiver based on the frequency (1 to 4) and severity (1 to 3) of symptoms, and a composite domain score is calculated by multiplying frequency and severity (range: 1-12). Additionally, caregiver distress for each positive symptom domain is rated on a 6-point scale (0 = not at all distressing, 5 = extremely distressing). In this study, the three NPI domains assessed were agitation/aggression, irritability/lability, and aberrant motor behavior. Higher scores indicate greater severity and frequency of neuropsychiatric symptoms.

Time frame: Baseline (current study), Week 52

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The CGIS is an observer-rated scale that measures illness severity. The CGIS-Agitation is a 7-point (1-7) scale (1 = normal, not at all ill; 7 = extremely ill) that assessed the severity of agitation in this study. Higher scores indicate severe agitation, while the lower scores indicate little or no agitation.

Time frame: Baseline (current study), Week 52

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The CMAI is used to assess the frequency of manifestations of agitated behaviors in elderly persons. It consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. Each of the 29 items is rated on a 7-point scale of frequency (1 = never, 2 = less than once a week but still occurring, 3 = once or twice a week, 4 = several times a week, 5 = once or twice a day, 6 = several times a day, 7 = several times an hour). The ratings are based on the 2 weeks preceding assessment of the CMAI. Higher scores indicate higher frequency of agitated behaviours while lower scores indicate lower frequency of agitated behaviours.

Time frame: Baseline (current study), Week 64

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The DEMQOL is a validated scale used to assess health-related quality of life in individuals with dementia and their caregivers. It includes two versions: a 28-item version completed by the participant (DEMQOL), and a 31-item proxy version completed by the caregiver (DEMQOL-proxy). Each item is rated using a 4-point scale to reflect the frequency or severity of health-related concerns: 1 = A lot, 2 = Quite a bit, 3 = A little, 4 = Not at all. Total score is derived by sum of all item scores, excluding item 29 of DEMQOL and item 32 of DEMQOL-proxy. Lower scores indicate better quality of life.

Time frame: Baseline (current study), Week 52

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life. It consists of two components: a descriptive system and the EuroQol Visual Analogue Scale (EQ VAS). The descriptive system covers five health dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-level scale: 1 = No problems, 2 = Slight problems, 3 = Moderate problems, 4 = Severe problems, 5 = Extreme problems. The EQ VAS component allows participants or caregivers to rate the individual's overall health on a vertical scale from 0 (the worst imaginable health state) to 100 (the best imaginable health state). Only participants from Study 17-AVP-786-305 with a MMSE score of 10 or higher at the baseline visit were planned to complete the participant-rated version.

Time frame: Baseline (current study), Week 52

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The mADCS-CGIC-Agitation is used to assess agitation in individuals with Alzheimer's disease. It includes questions focused on agitation and uses a semi-structured interview format involving both the participant and their caregiver. The clinician rates the participant's overall clinical status using a 7-point scale: 1 = marked improvement, 2 = moderate improvement, 3 = minimal improvement, 4 = no change, 5 = minimal worsening, 6 = moderate worsening, and 7 = marked worsening. Lower scores indicate improvement in agitation symptoms, while higher scores indicate worsening.

Time frame: Baseline (current study), Week 64

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The PGIC is a 7-point scale used to assess perceived treatment response, as evaluated by the participant's caregiver. The caregiver rates the overall change in the participant's condition since the start of treatment. The PGIC score ranges from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Lower scores reflect greater improvement, while higher scores indicate worsening of the participant's condition.

Time frame: Baseline (current study), Week 52

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

The RUD is a standardized tool used to estimate healthcare costs associated with dementia. It assesses the use of both formal and informal (e.g., hospitalizations, doctor visits, living assistance, and unprofessional caregiver time) healthcare resources. The instrument is administered as a semi-structured interview with the participant's primary caregiver. It consists of two main sections: one evaluates the caregiver's burden, including lost work and leisure time, and the other documents the participant's use of healthcare services. Total healthcare costs are calculated by multiplying the quantity of resources used (e.g., number of doctor visits, hours of caregiver, nights in accommodation) by unit costs. Higher estimated totals reflect greater economic impact associated with dementia care.

Time frame: Baseline (current study), Week 52

Population: Due to discontinuation of development of the AVP-786 compound, no data was collected and analyzed as planned for this pre-specified secondary efficacy outcome measure as noted in the SAP. Only safety data was collected and analyzed.

Concomitant medications were defined as any medications taken on or after the date of first dose of study drug in Study 15-AVP-786-303 or that are ongoing concomitant medications from Studies 15-AVP-786-301, 15-AVP-786-302, 17-AVP-786-305, and 12-AVR-131.

Time frame: Baseline (current study) up to 64 weeks